Calcium channels convert electrical signals in the cell membrane into an increase in intracellular calcium, thereby activating many crucial physiological processes, including muscle contraction, hormone secretion, neurotransmission, synaptic plasticity, regulation of enzymatic activites and gene expression. Calcium channels can be classified into a number of types and subtypes, for example L-(or Cav1), P/Q-(or Cav2.1), N-(or Cav2.2), R-(Cav2.3) and T-(or Cav3) types. T-type calcium channels can, for example, be subclassified into α1G (or Cav3.1), α1H (or Cav3.2), and α1I (or Cav 3.3) T channels. See, e.g., Catterall et al., Annu. Rev. Cell Dev. Biol. 16, 521–55, (2000); and Perez-Reyes et al., Physiol. Rev. 83, 117–161, (2003).
Physiologically, calcium channels are distributed widely. For example, T-type channels can be found in neurons, the heart, kidney, smooth muscle, skeletal muscle, sperm, and endocrine tissues (such as adrenal and pituitary glands and the pancreas). Consequently, T-type calcium channels are thought to be involved in autonomic nervous functions, and in regulation of cardiovascular activities such as heart rate, arterial and venous smooth muscle innervation and tone, pulmonary rate, and other critical processes.
Due to their role in modulating many physiological processes, abnormal or unwanted calcium channel activity is also associated with many disease states. Agents which antagonize or agonize the activity of calcium channels have been shown to be useful as therapies for treating a wide variety of diseases and disorders. See, e.g., WO 99/23072; EP 0545845; and Kochegarov et al., Expert Opin. Ther. Patents, 12, 243–287, (2002).
L-channel blockers have a well established role in the treatment of diseases such as hypertension and angina (see e.g. Mannhold et al., Drugs of Today, 30, 103–122, 1994). Compounds that have exclusively or predominantly T-channel blocking activity or that have dual L- and T-channel blocking activities are considered to be useful for the treatment of hypertension, angina, arrhythmia, congestive heart failure, renal disease, epilepsy, neuropathic pain, and other diseases and conditions. See, e.g., Perez-Reyes et al., Physiol. Rev. 83, 117–161 (2003) and WO 03/07953.
T-channel blockers are also useful for the treatment of sleep disorders, mood disorders, depression, migrane headache, neuronal excitability disorders, hyperaldosteronemia, preterm labor, urinary incontinence, brain aging, or neurodegenerative related diseases such as Alzheimer's disease. See, e.g., WO 01/02561; WO 00/02455; JP11035483 and Chemin et al., J. Physiol., 540, 3–14, (2002). Additionally, T-type calcium channels play a role in pancreatic beta-cell insulin secretion. Therefore, T-type blockers may be useful for treatment of hypo- and hyperinsulinemia and the treatment and/or prevention of type 1 and type 2 diabetes as well as microvascular or macrovascular diseases associated with diabetes. See, e.g., Bhattacharjee et al., Endocrinology, 138, 3735–40, (1997) and WO 00/15845. T-type calcium channel blockers may also be useful in the treatment of cancer. See, e.g., WO 00/59882 and WO 01/019845.
Drugs such as mibefradil and efonidipine which block both T and L calcium channels have been shown to be useful or potentially useful in a variety of disease states. Such drugs may have therapeutic advantages over calcium channel blockers that predominantly target the L-channel. For example, mibefradil was shown to be useful for the treatment of hypertension and angina and did not show the negative side-effects including inotropy, reflex tachycardia, vasoconstrictive hormone release or peripherial edema, which are often shown by predominantly L-channel blockers. See, e.g., Sandman et al., J. Clin. Basic Cardiol., 2, 187–201 (1999) and Glasser et al., J. Clin. Pharmacol., 38, 659–669 (1998). Also, mibefradil has been shown to be potentially cardioprotective (see e.g. Villame, Cardiovascular Drugs and Therapy, 15, 41–48 (2001) and Ramires, et al., J. Mol. Cell Cardiol., 30, 475–483, (1998)) and renal protective (see e.g. Honda, J. et al., Hypertension, 19, 2031–2037 (2001); Baylis et al., Am. J. Kidney Dis., 38, 1292–1297 (2001); Qiu, et al., J. Hypertension, 1489–1495 (1999); and Karam et al., Hypertension, 34, 673–678, (1999)). Also, unlike most predominant L-channel blockers, mibefradil has been shown to be potentially useful in the treatment of heart failure. See, e.g., Clozel, et al., Proceedings of the Association of American Physicians, 111, 429–437 (1999); Mulder, et al., Journal of the American College of Cardiology, 29, 416 (1997); and Meissner, et al., Exp. Biol. Med 227, 336–44, (2002). Mibefradil may also be useful in the treatment of atherosclerosis (see e.g. Mason, et al., Biochemical Pharmacology, 55, 1843–1852, (1998)) and inflammation (see, e.g., Bilici, et al., Pharmacological Research, 527–531 (2001)). Efonidipine, another calcium channel blocker with a combination of T- and L-channel blocking activities, also shows therapeutic advantages over pure L-channel blockers. See, e.g., Harada, et al., Circ. J. 67, 139–145 (2003); Hayashi, et al., Amer. Heart J., 16, 116–122 (2003); and Tanaka, et al., Cardiovascular Drug Reviews, 20, 81–92 (2002).